Abstract
Rationale
Cough is a commonly reported symptom in idiopathic pulmonary fibrosis (IPF) that negatively impacts patient-reported quality of life (QoL). However, both the burden of cough at diagnosis and the behavior of cough over time have not been systematically described in patients with IPF.
Objectives
By utilizing data prospectively collected as part of the PROFILE study, we sought to assess cough burden and the impact that this has on QoL within a cohort of patients with newly diagnosed IPF. We also reexamined the previously described relationship between cough and mortality and the association of cough with the MUC5B promoter polymorphism.
Methods
The PROFILE study is a multicenter, prospective, observational, longitudinal cohort study of incident IPF. Scores on the Leicester Cough Questionnaire (LCQ) were recorded at baseline in 632 subjects and then repeated 6 monthly in a subset (n = 216) of the cohort.
Results
The median LCQ score at diagnosis was 16.1 (interquartile range, 6.5). LCQ scores remained stable over the subsequent year in the majority of patients. There was a weak association between LCQ score and baseline lung function, with worse cough-related QoL associated with more severe physiological impairment. Cough scores were not associated with subsequent mortality after correcting for baseline lung function. Furthermore, there was no relationship between LCQ score and MUC5B promoter polymorphism status.
Conclusions
The burden of cough in IPF is high. Although cough is weakly associated with disease severity at baseline, cough-specific QoL, as measured by the LCQ, confers no prognostic value. Cough-specific QoL burden remains relatively stable over time and does not associate with MUC5B promoter polymorphism.
Keywords: cough, quality of life, interstitial lung disease, MUC5B
Idiopathic pulmonary fibrosis (IPF) is an inevitably progressive disease associated with considerable morbidity and mortality. The incidence of IPF continues to rise (1, 2), and although antifibrotic therapies slow disease progression, they do not positively affect quality of life (QoL), and symptom control remains a significant unmet need (3). Cough is one of the most common symptoms reported by patients with IPF and negatively impacts health-related QoL (4).
Although it is accepted that cough is a significant and common problem in IPF, no reliable data on the frequency or severity of this symptom exist. The burden of cough at the time of diagnosis of IPF is poorly understood, as is the relationship between cough and IPF disease progression. Existing studies report that somewhere between 50% and 80% of patients with IPF experience chronic cough (5). These data are mainly based on small cohorts and single-center retrospective or registry data. The inherent biases associated with these data sources almost certainly explain some of the reported variability in estimates of cough prevalence. Differing definitions, reporting, and measuring strategies for cough further confound the interpretation of the existing literature.
Mechanisms underlying cough in IPF also remain opaque. There are several proposed disease-specific mechanisms by which cough could be driven, including architectural distortion of the airways, mucus hypersecretion, and heightened neurogenic cough reflex (6). A genetic component to cough has previously been postulated with a small retrospective study suggesting an increased burden of cough in patients with an SNP affecting the MUC5B gene (rs35705950) (7, 8); this same SNP has been identified as the most common risk allele for the development of sporadic IPF. In addition to these potential disease-specific drivers, there are several common comorbidities seen in IPF that may also contribute to the burden of cough, including obstructive sleep apnea, gastroesophageal reflux, and concomitant airway diseases (9).
Given the limited understanding of the burden of cough in IPF, we set out to characterize cough and its impact on QoL at baseline and longitudinally in individuals with an incident diagnosis, as part of the multicenter PROFILE study. We also examined the relationship between cough and mortality and the association of cough with the MUC5B promoter polymorphism.
Methods
Study Design
Individuals with IPF diagnosed within the preceding 6 months were recruited prospectively as part of the PROFILE study through two coordinating centers in the United Kingdom, Nottingham University Hospital and the Royal Brompton Hospital. Approval for the study was obtained from the local research ethics committee (10/H0402/2 and 10/H0720/12), and written informed consent was obtained from all subjects. Patients were assessed at baseline; at 1, 3, and 6 months; and then annually for 3 years. Survival status was then reassessed on June 30, 2020. Patients underwent tests for lung function (forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DlCO]) at baseline and at 6, 12, 24, and 36 months and completed a cough-related QoL questionnaire (Leicester Cough Questionnaire; LCQ) at baseline. Subjects recruited through the Royal Brompton Hospital also completed the LCQ at 6 and 12 months and annually thereafter for 3 years. Recent (within 4 wk) history of self-reported upper or lower respiratory tract infection or acute exacerbation precluded subjects from being recruited to the PROFILE study. The following parameters were recorded at baseline: age, gender, smoking status, body mass index (BMI), the presence of gastroesophageal reflux disease, and concomitant therapy with proton pump inhibitor and angiotensin-converting enzyme inhibitor. During the follow-up period, initiation of antifibrotic therapy was documented.
LCQ
The LCQ is a cough-specific QoL questionnaire that was validated in patients presenting with chronic cough (10). The questionnaire comprises 19 items, of which 8 are assigned to the physical domain; 7, to the psychological domain; and 4, to the social domain. The score range is 3 to 21, with higher scores indicating a better QoL.
MUC5B Genotyping
DNA was extracted from peripheral whole blood using the Gentra Puregene extraction kit (QIAGEN). A TaqMan SNP genotyping assay (Thermo Fisher Scientific) was used to genotype the MUC5B SNP rs35705950. Reactions were performed in 384-well plates, and fluorescence was read using an Applied Biosystems Viia7 Sequence Detection System. From this, the MUC5B promoter polymorphism was analyzed and grouped as being either wild type (genotype GG), heterozygous for the minor allele (genotype GT), or homozygous for the minor allele (genotype TT).
Statistical Analysis
Continuous variables are presented as mean ± standard deviation or median ± interquartile range (IQR) as appropriate, and categorical variables are presented as median ± IQR. Time-to-event variables were assessed using the Kaplan-Meier method and compared with the log-rank test. The relationship between LCQ score and survival was assessed using a multivariate Cox proportional hazard model adjusted for age, gender, smoking status, and baseline FVC and DlCO. Differences between subject groups were evaluated with the use of the Mann-Whitney test for continuous variables, and Fisher’s exact test was used for categorical variables. Spearman’s rho was used to calculate correlations between continuous variables.
Disease progression was defined as previously described for the PROFILE study (11). Subjects were considered to have progressed if they died from any cause within 12 months of study enrollment or if they had a decline in FVC of ⩾10% at 12 months. Missing lung function data were not imputed. For subjects missing 12-month data, progression status was adjudicated by the local principal investigator (T.M.M. and R.G.J.), who was blinded to other study results.
All analyses were performed with the using R Statistical Software (v4.2.3; R Core Team 2021). A two-sided P < 0.05 was considered to indicate statistical significance.
Results
Study Population
The PROFILE study enrolled 632 patients, with the last patient recruited in 2014. For the purpose of survival analyses, subjects were censored on June 30, 2020. Patient demographics at baseline are described in Table 1; 8.8% of the participants commenced antifibrotic therapy (53 pirfenidone, 3 nintedanib) during the follow-up period.
Table 1.
Baseline demographics and clinical information
| Demographic | Data |
|---|---|
| Age, yr, mean (±SD) | 70.2 (8.3) |
| Male, n (%) | 487 (77.1) |
| Smoking status, n (%) | |
| Current | 32 (5.1) |
| Ex-smoker | 398 (63.1) |
| Never smoked | 201 (31.9) |
| BMI, kg/m2, n (%) | |
| <18.5 | 7 (1.1) |
| 18.5–24.9 | 124 (19.6) |
| 25.0–29.9 | 285 (45.1) |
| ⩾30.0 | 216 (34.2) |
| Lung function, mean (±SD) | |
| FEV1, (L/s) | 2.2 (0.6) |
| FVC (L) | 2.8 (0.9) |
| FEV1:FVC | 0.81 (0.07) |
| DlCO, ml CO/min/mm Hg | 3.8 (1.4) |
| FEV1, % predicted | 78.2 (17.1) |
| FVC, % predicted | 74.1 (17.6) |
| DlCO, % predicted | 48.6 (16.1) |
| GAP stage, n (%) | |
| 1 | 236 (37.3) |
| 2 | 275 (43.5) |
| 3 | 121 (19.1) |
| Gastroesophageal reflux, n (%) | 307 (48.6) |
| PPI therapy, n (%) | 176 (27.8) |
| Angiotensin-converting enzyme inhibitor therapy, n (%) | 107 (16.9) |
| Antifibrotic therapy, n (%) | 56 (8.8) |
Definition of abbreviations: BMI = body mass index; DlCO = diffusing capacity of the lung for carbon monoxide; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GAP = gender, age, physiology; PPI = proton pump inhibitor.
Data are presented as number (%) or mean (±SD).
Baseline Cough
At baseline, the median LCQ score was 16.1 (IQR = 6.5), with scores skewed toward the higher end of the scale (i.e., lower cough burden; see Figure E1 in the data supplement). The median scores for the physical, psychological, and social domains were 5.1 (IQR = 1.7), 5.0 (IQR = 2.4), and 5.0 (IQR = 2.5), respectively. Both the FVC (R2 = 0.14, P < 0.001) and DlCO (R2 = 0.2, P < 0.001) demonstrated weak but statistically significant positive correlations with baseline cough burden (see Figure E2), with more severe physiological impairment being associated with greater impairment of cough-related QoL as measured by the LCQ. Despite the relationship between baseline FVC, DlCO, and LCQ score, there was no difference in LCQ score between individuals with stable or progressive disease at 12 months (see Figure E3).
In a univariate model, greater cough burden was associated with worse survival (hazard ratio, 0.97; 95% confidence interval = 0.95–0.99; P = 0.013). However, this association did not hold when correcting for age, gender, baseline lung function, and smoking history in a multivariable Cox proportional hazards model (hazard ratio, 1.01; 95% confidence interval = 0.97–1.03, P = 0.34) (see Table E1). To investigate the association between cough and disease severity, we then split the cohort into three groups on the basis of cough severity: LCQ scores were ⩽10 for the “worst” group, >10 to ⩽14 for the “moderate” group, and >14 for the “mildest” group (12). Those subjects with the worst cough impact were younger and had more impaired lung function, although there was no difference in gender between the groups (see Table E2). There was no significant difference in survival between groups over time, when either split based on cough severity (Figure 1) or tertiles (see Figure E4).
Figure 1.
There is no association between Leicester Cough Questionnaire (LCQ) score at baseline and survival in idiopathic pulmonary fibrosis. Kaplan-Meier survival curves according to baseline LCQ score split by disease severity (LCQ scores were ⩽10 for the “worst” group, >10 to ⩽14 for the “moderate” group, and >14 for the “mildest” group). There was no significant difference in survival demonstrated between groups.
On genotyping for the MUC5B promoter polymorphism (rs35705950), the minor allele (T) was present in 343 (61%) patients, the heterozygous minor allele (GT) was present in 300 (53.5%) patients, and the homozygous minor allele (TT) was present in 43 (7.7%) patients. There was no statistically significant difference in cough among the three MUC5B genotypes (Figure 2).
Figure 2.
There is no difference in cough on the basis of MUC5B genotype. Baseline total LCQ scores are stratified by MUC5B genotype. LCQ = Leicester Cough Questionnaire.
Longitudinal Cough Burden
A total of 216 subjects in the PROFILE cohort had LCQ scores recorded at multiple time points (at baseline and at 6 mo, and 12 mo). These data were used to assess the stability of cough burden over time. To visually interrogate the apparent stability of LCQ scores over time, we separated subjects again into three groups on the basis of cough severity (LCQ scores were ⩽10 for the “worst” group, >10 to ⩽14 for the “moderate” group, and >14 for the “mildest” group). The general stability in LCQ score can be appreciated in alluvial plots (Figure 3), which demonstrate that, over the course of 12 months, there is relatively little movement of subjects between cough severity groups. This stability is again seen when splitting the cohort into tertiles (see Figure E5).
Figure 3.
Stability of Leicester Cough Questionnaire (LCQ) scores over time. When split into groups on the basis of disease severity (LCQ scores were ⩽10 for the “worst” group, >10 to ⩽14 for the “moderate” group, and >14 for the “mildest” group), there is little movement between groups at baseline and at the 6- and 12-month time points.
When separating subjects by IPF disease behavior, those with stable disease demonstrated stability in cough-related QoL with a 12-month change in LCQ score of 0.80 (±3.8). Subjects with progressive disease, however, experienced worsening cough-related QoL with a 12-month change in LCQ score of −2.2 (±5.0), P < 0.001 for the comparison between stable and progressive groups.
Discussion
This is the largest study to prospectively assess the impact of cough in IPF. Using LCQ scores, we have demonstrated that the burden of cough in IPF is greater than has been described in the general population reporting chronic cough (13). At baseline, the impact of cough in individuals with IPF is weakly associated with physiological measures of disease severity (e.g., FVC and DlCO), but it is not associated with MUC5B status, nor, once corrected for lung function, does it predict mortality. This lack of association with MUC5B genotype is in contrast to a previously published study that included a cohort of 136 individuals (14). Unlike chronic idiopathic cough, which tends to show a female preponderance, there were no gender differences in cough severity in IPF (15). Longitudinal assessment of LCQ data suggests that the impact of cough-related QoL changes little over time for the majority of patients with IPF. Change in cough-related QoL that does occur is associated with worsening lung function.
We have confirmed previously reported associations between worse baseline lung function and greater impairment of cough-specific QoL. Although the association was relatively weak, it was statistically robust. Given the nature of the LCQ, it is not possible to determine whether this association reflects a genuine link between cough frequency or intensity and disease severity or whether worse lung function simply amplifies the impact of preexisting cough on QoL. Studies utilizing objective cough counting will help address this question.
When following longitudinal LCQ scores over 12 months, we observed a mild worsening in cough-related QoL in individuals with progressive IPF. However, the magnitude of change (−2.2 units over 12 mo) is only marginally greater than the minimally clinically important difference in LCQ scores (16). When separating the PROFILE cohort according to thresholds of LCQ score severity, we saw very limited crossover between groups over the course of 1 year. Although some fluctuation in cough is probably to be expected, we hypothesized that this observation might reflect different endotypes of cough in individuals with IPF; that is, patients with severe cough at diagnosis are likely to be troubled by cough throughout their disease course, whereas those with minimal cough are very unlikely to develop severe cough as a feature of their disease, even as fibrosis progresses over time.
We speculate that the limited movement of subjects between cough severity groups may reflect processes independent of pulmonary fibrosis. This could be important when developing targeted therapies and when considering trial design. The cough reflex is mediated by sensory neurons in the airways that are activated by chemical and mechanical stimuli. Individuals with IPF have been demonstrated to have an enhanced cough response to chest wall percussion (17) and to inhaled chemical irritants such as capsaicin, raising the possibility that enhanced neuronal sensitivity is involved in IPF cough (18). Whether the common comorbidity of gastroesophageal reflux is also an important driver of cough remains to be established (19, 20). Nonetheless, targeting these neuronal pathways in chronic cough is a promising therapeutic option that may also work in IPF. A recent study targeting P2X3 ion channels on airway nerves in IPF reported a trend toward an effect in a post hoc analysis (21). Thalidomide, which is known to influence peripheral nerve function, has been shown to improve cough-specific QoL in patients with IPF (22). Other antitussive strategies currently being tested with IPF are aimed at the suppression of cough centrally (23, 24).
The prospective nature of the PROFILE cohort allowed us to definitively demonstrate that baseline cough impact, as measured by the LCQ, does not independently predict subsequent disease progression or mortality in patients with IPF. The finding on mortality is contrary to the findings of previous studies, which were mostly conducted in smaller, registry-based or retrospective cohorts (25). These studies may well have been confounded by disease severity, which, as we have shown, correlates with cough and is itself predictive of mortality. Furthermore, Ryerson and colleagues assessed the presence of cough as a dichotomous variable, and one-third of the patients did not have progression data available. Lee and colleagues recently performed a retrospective assessment of LCQ across a range of interstitial lung diseases (ILDs) drawn from the Pulmonary Fibrosis Foundation Patient Registry (12). They reported that every 1-point decrease in LCQ score was associated with a 7.4% increase in risk of death when corrected for baseline disease severity. The difference in the relationship between LCQ scores and mortality when comparing their study with the data we present from PROFILE could be accounted for by Lee and colleagues’ inclusion of multiple interstitial lung disease subtypes. Additionally, the Pulmonary Fibrosis Foundation Patient Registry population included individuals with prevalent disease, and as such, the cohort consisted of subjects with predominantly late-stage fibrotic lung disease, with more than 60% requiring home oxygen (26). This contrasts with the PROFILE population, who, on average, had well-preserved lung function at study entry, with a mean DlCO of 48.6% predicted and an FVC of 74.1% predicted.
The prospective design of PROFILE and the fact that recruited subjects had an incident diagnosis of IPF are clear strengths of our study and provide reassurance that the reported findings are generalizable to patients with IPF seen in real-world practice. Nonetheless, our work has a number of limitations. The LCQ, although used extensively as a cough-related QoL tool in pulmonary fibrosis trials, has never been formally validated for IPF. Furthermore, the LCQ is an indirect measure of cough developed to quantify cough-related QoL. In chronic idiopathic cough, LCQ score has been shown to correlate well with daytime cough frequency measured using objective cough monitoring (27). However, it is conceivable that, in individuals with established lung disease, the measurement of cough-related QoL could be confounded by physical or mental/emotional symptoms related to chronic respiratory impairment. Longitudinal studies using objective cough frequency measurement in individuals with IPF are required, as these are not confounded by a patient’s subjective evaluation of cough and may, therefore, provide additional insights regarding the nature of cough in this disease group. Furthermore, the majority of our cohort did not receive antifibrotic therapy, and its effect on cough is unknown.
In summary, the burden of cough is high in IPF and has a major effect on health-related QoL. Although cough impact is associated with physiological measures of disease severity, LCQ score at baseline does not independently convey prognostic value. As the severity of cough in individuals with IPF remains relatively stable over time, patients with severe cough at diagnosis continue to experience impaired cough-related QoL throughout the course of their illness. Thus, there remains a huge unmet need for treatments that target the debilitating symptom of cough in some individuals with IPF.
Footnotes
Supported by GlaxoSmithKline Research and Development and the United Kingdom Medical Research Council and by the NIHR Manchester Biomedical Research Centre (to J.A.S.).
Author Contributions: P.S., Z.W., W.A.F., G.S., R.B., C.S., E.A.R., S.R.J., R.G.J., M.G.B., J.A.S., T.M.M., and P.L.M. contributed to recruitment, data collection, analysis, and preparation of the final manuscript. I.D.S. and D.J.F.S. contributed to the final manuscript.
This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Author disclosures are available with the text of this article at www.atsjournals.org.
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